Preparation of phe



V solved in 500 cc. ofabsolute alcohol.

Patented Sept. 12, 1944 UNITED STATE enames Marc 'TJ Inman;' Nyack, and-William 'P."

Bitler; i

' "'Haverstrafw, N. Y., assi'gndrs to'lKay-lries g 1 Chemical's,1Inc.;'West Haverstraw, N. Y., a corporationof Ndw york l No Drawing. pplicationseptember 12, 1941,; f I s S e1 i a.l-No.41ll,5.7 7 3 9 Claims (01. egg-525,7)

phenyl ethyl malonic ester takes Place, resulting in a large decrease in yield due to the formation of undesired Icy-products.

It has now been found that these prior art disadvantages can be overcome by adding sodium ethylate solution gradually to the reaction mixture and controlling the temperature of reaction with the result that the extent of cleavage of the phenyl ethyl malonic ester is substantially suppressed, although the conversion into the desired product is somewhat lowered. The recoverable yield of the finished product is greatly increased and the undesirable side reactions are substantially done away with.

In the practice of the process according to the present disclosure, a reaction mixture of phenyl ethyl malonic ester with an appreciable excess of urea, in a suitable solvent, such as absolute ethyl alcohol, i prepared and introduced into a convenient reaction vessel. The condensing agent, usually sodium ethylate, in absolute ethanol, is added slowly, and desirably with cooling, to the reaction mixture under conditions such that any excess of sodium present at a given instance of time is minimized, and, the amount of extent of of by-products. The net result of this procedure is that although a relatively lesser yield'of phenobarbital is secured from the reaction, the saving in unconverted phenyl ethyl malonic ester offsets the decreased yield, and a commercially practicable process gives a purer product at appreciably reduced costs.

The followingspecific example of the process is given by way of illustration:

528 g. phenylethyl malonic diethyl ester is dis- There is then added 140 g. urea to the mixture. To this mixture there is then added a solution of 57.5 g.

sodium in 1000 ce. l absolute alcohol; at such a ate that one hau the somtion is added during the first hour,'al quarter the second Hour; an eighth the third hour, and the final eighth 'duririgiithe iourthhour; As 'the sodium' alcoholajte solut on is added, alcohol is distilled iro il the reaction ifniX- tureT -Up tothis pointfthe .te'mperature of the reactioninixturewm vary between 84-86.C.- Appn'canon jor vacuum' may be. necessary so as not i to exceed a l'iquid t'fr'ip'erature of 368 .C. 1 When the alcohol has all been removed, 250 ccixylolis added to the mixture. The reaction mixture is cooled to room temperature and three liters of Water added. The xylene layer was separated and the water solution washed with another 200 cc. portion of xylene. There is then added to the water solution a 10% excess of a 50% by weight solution of sulphuricacid. The phenobarbital is precipitated as nearly white fluffy crystals, which are filtered off. When dried, they showed phenobarbital by titration. This product may be purified by recrystallization. The unreacted esterin the xylene solution was recovered by distilling ofi the xylene, and then the phenylethyl malonic ester.

It will now be appreciated that there has been disclosed a novel process for the manufacture of phenobarbital by condensing phenyl ethyl malonic ester with urea under conditions such that the normally undesired side reactions caused by cleavage of the malonic ester are avoided by maintaining the amount of sodium present at any time in the reaction below that at which appreciable decomposition of malonic ester is efiected.

What is claimed is: p

1. In the process for the manufacture of phenobarbital by condensing phenyl malonic ester with urea, without cleavage of the malonic ester and in the presence of sodium ethoxide as a condensing agent, the improvement comprising adding aliquot portions of sodium ethoxide to the reaction mixture of the ester and urea by timed additions so that the sodium alcoholate is never present in amounts in excess of those needed to effect the condensation and thereby precludes cleavage reaction of the soethyl and in amount sufficient only 'to effect the desired condensation, and thereby avoid cleavage of the malonic ester.

3. The method of preparing phenobarbital comprising dissolving phenyl ethyl malonic diethyl ester in absolute alcohol, adding reactive amounts of urea to the so formed ester solution, and then adding aliquot portions of sodium ethoxide to the reaction mixture in amount such that the sodium ethoxide is never present in excess of the amount needed to eflect'the condensation and thus no free sodium ethoxide is availa-..

ble at any time to effect cleavage of the malonic ester.

4. Method according to claim 3, in which alcohol is removed concomitantly with the introduction of the sodium ethoxide.

5. Method according to claim 3, in whichso} dium ethoxide is added to the ester solution in a fourhour time periodas follows: one-half during the first hour; one-quarter during the second hour; one-eighth during each of the third and fourthhours. w c, ,.V

6. Method according. to claim 3, in which the dealcoholized reaction products are purified by washing with xylol, then with water, separating the wash water and washing with xylol, and the phenobarbital precipitated out of the water layer by strong sulphuric acid, filtered, dried, and recrystallized. c i

7. The method of preparing phenobarbital comprising dissolving 528 g. phenyl ethyl malonio diethyl ester in 500 cc. of absolute alcohol; adding 140 grams of urea to the alcoholic ester solution; condensing the urea-ester with alcoholic sodium ethoxide comprising 57.5 g. sodium dissolved in 1000 cc. absolute alcohol, the ethoxide solution being added over a'four hour period so that the ethoxide is never present in amounts in excess of that needed to effect the condensation and thereby avoid cleavage of the malonic ester, the

" evolved alcoholate being continuously removed .while the reaction temperature is desirably maintained within aLtemperature range of 84-86 C.; washing the reacted mixture'with 250 cc. xylol, cooling to room temperature, washing with water and'removing separated xylene; adding 200 cc. 

